My research proposal will investigate the role of costimulatory molecules, in particular CTLA-4, in tolerance induction and autoimmunity. Costimulatory molecules have a pivotal role in T cell activation and induction of tolerance. The striking phenotype of the CTLA-4-deficient strain demonstrates a key role for CTLA-4 in down-regulating T cell activation and suggests that CTLA-4 is involved in regulating autoimmune responses. In this proposal, I will investigate the in vivo role of CTLA-4 to exogenous and autoantigens using novel transgenic strains as a tool. Our studies will examine whether CTLA-4 regulates T helper cell differentiation in response to exogenous administration of antigen and whether it is possible to tolerize CTLA deficient T cells. Additionally, the role of CTLA-4 in the development of autoimmune responses will be examined using altered peptide ligands and TCR transgenic mice. These studies should provide insights into the regulatory role of CTLA-4 in tolerance and autoimmunity.